WO2019035008A1 - Inhibiteurs de cdk4/6 et leur utilisation - Google Patents

Inhibiteurs de cdk4/6 et leur utilisation Download PDF

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Publication number
WO2019035008A1
WO2019035008A1 PCT/IB2018/056140 IB2018056140W WO2019035008A1 WO 2019035008 A1 WO2019035008 A1 WO 2019035008A1 IB 2018056140 W IB2018056140 W IB 2018056140W WO 2019035008 A1 WO2019035008 A1 WO 2019035008A1
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alkyl
fluoro
haloalkyl
heterocyclyl
compound
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PCT/IB2018/056140
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English (en)
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Yuntao Song
Xiaoqi Chen
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Beijing Xuanyi Pharmasciences Co., Ltd.
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Application filed by Beijing Xuanyi Pharmasciences Co., Ltd. filed Critical Beijing Xuanyi Pharmasciences Co., Ltd.
Priority to US16/639,412 priority Critical patent/US11351170B2/en
Priority to CN201880052794.2A priority patent/CN111315379A/zh
Publication of WO2019035008A1 publication Critical patent/WO2019035008A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure relates to novel compounds having certain biological activities that include, but are not limited to inhibiting cyclin-dependent kinases.
  • the present disclosure relates to aminopyrimidine compounds of formulae (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salts and derivatives thereof, pharmaceutical compositions thereof, and method of using the same.
  • the restriction point is controlled by the retinoblastoma pathway (CDK4/CDK6- cyclin Dl-Rb-pl6/ink4a).
  • the retinoblastoma protein (Rb) is a tumor suppressor that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors, and the restriction point is controlled by phosphorylation of Rb by the CDK4 and CDK6 kinases.
  • the central role of the Rb pathway in controlling cellular proliferation is highlighted by its frequent dysregulation in human cancer. The anticancer clinical benefit was demonstrated by palbocilib in breast cancer and palbocilib was approved by FDA in 2015. There are some CDK inhibitor compounds that have gone through or currently undergoing clinical trials.
  • Chemotherapeutic compounds tend to be non-specific and, particularly at high doses, toxic to normal, rapidly dividing cells. This often leads to a variety of side effects, e.g., bone marrow suppression, adverse effect over healthy cells such as renal epithelial cells.
  • CDK4/6 inhibitors There has been extensive research in discovering CDK4/6 inhibitors, in view of the number of pathological responses that are mediated by CDK4/6; however, there remains a continuing need for discovering therapeutically effective inhibitors of CDK4/6, for example, for the treatment of hyper-proliferative diseases, or transient protection of normal cells during chemotherapy. Additionally, discovery of novel CDK inhibitors will be useful in combination of other anticancer agents considering the fact that many kinase inhibitors develop resistance.
  • the present disclosure relates to compounds of formula (A) or
  • X 1 and X 2 are each independently CH or N;
  • R 1 is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF3, -OCH2CF3, -OCH2CHF2, -CF3, - CHF2, -CHO, -CH2OH, -CONH2, -CC Me, -CONHMe, -CONMe 2 , or cyano;
  • R 2 is selected from hydrogen, fluoro, chloro, methyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF3, -CF3, -CHF2, -CH2OH, -CONH2, -CONHMe, -CONMe2, or cyano;
  • R 3a and R 3b are each independently H, -Ci-6 alkyl, or -Ci-6 haloalkyl; or
  • R 3a and R 3b taken together with the carbon atom to which they are both attached, form a 3-7 membered ring, optionally containing up to two heteroatoms selected from O, S(0) x , or NR 11 , or forms a 7-12 membered heterobicyclic ring which may be fused, bridged or spiro, and includes one to three heteroatoms selected from O, S(0) x , or NR 11 , and wherein the 3-7 membered ring and the 7-12 membered heterobicyclic ring are optionally substituted with up to three substituents selected from hydroxyl, -Ci-6 alkoxy, -Ci-6 hydroxyalkyl, Ci-6 alkoxy-Ci-6 alkyl-, Ci-6 alkoxy-Ci-6 alkoxy-, C2-6 hydroxyalkoxy, oxo, thiono, cyano or halo;
  • Y is -G-, -L-, -G-L-, -L-G-, -L-G-L-, -G-L-G-, -L-G-L-G-, or -G-L-G-L-;
  • R 6 is H, -Ci-6 alkyl, -Ci-e haloalkyl, -C3-12 cycloalkyl, -NR n R 7 , or a
  • L is a divalent linker that can be connected in a chain in either direction, which is selected from absent, -(CR a R b ) P -, -(CR a R b ) P -cycloalkyl-(CR a R b ) P -, or -(CR a R b ) P - heterocyclyl-(CR a R b ) P -, wherein cycloalkyl and heterocyclyl can be optionally further substituted with up to three substituents selected from F, -OH, oxo, -C1-3 alkyl, -C1-3 haloalkyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or mo ⁇ holinyl; [21] R 7 is H, -Ci-6 alkyl,
  • R n is H or -Ci-6 alkyl
  • R a , R b and R° are each independently H, F, -Ci-6 alkyl, or -C 1-6 haloalkyl;
  • n 1, 2, or 3;
  • Y-R 6 does not comprise the following sequence in either direction: -0-(CR a R b )-0-, -0-(CR a R b )-NR n -, -O- (CR a R b )-S(0)x-, -NR n -(CR a R b )-N, -NR n -(CR a R b )-S(0) x -, or -S(0) x -(CR a R b )-S(0) x -.
  • Y-R 6 is not:
  • R 20 is H, methyl, ethyl, isopropyl, cyclopropyl, or -CH2CH2F;
  • R 24 is H or ethyl
  • R 26 is H, methyl, or ethyl
  • R 1 is selected from hydrogen, fluoro, chloro, methyl, or cyano
  • R 2 is selected from hydrogen, fluoro, or cyano
  • R 3a and R 3b are each independently H, -C1-3 alkyl, or -C1-3 haloalkyl; or
  • R 5 is independently selected from H, -C1-3 alkyl, F, CI, -CN, or -CD3;
  • R a and R b are each independently H, F, -C1-3 alkyl, or -C1-3 haloalkyl;
  • R 7 is H, -Ci-3 alkyl, -C1-3 haloalkyl, -C6-C12 aryl, C6-C12 aryl-Ci-C6 alkyl-, 5-12 membered heteroaryl, or 5-12 membered heteroaryl-Ci-C6 alkyl-, wherein -C6-C12 aryl, C6-Ci2 aryl-Ci-C6 alkyl-, 5-12 membered heteroaryl, and 5-12 membered heteroaryl- C1-C6 alkyl- can be optionally further substituted with up to three substituents selected from F, -OH, -C1-3 alkyl, -C1-3 haloalkyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or mo
  • R 1 is hydrogen, fluoro, chloro, methyl, or cyano.
  • R 2 is hydrogen, fluoro, or cyano.
  • L is a divalent linker that can be connected in a chain in either direction, which is selected from -(CR a R b ) P -, -(CR a R b ) P -cycloalkyl-(CR a R b ) P -, or -(CR a R b ) P -heterocyclyl- (CR a R b ) P -, wherein cycloalkyl and heterocyclyl can be optionally further substituted with up to three substituents selected from F, -OH, oxo, -C1-3 alkyl, -C1-3 haloalkyl, -CH2OH, - CH2CH2OH, -CH2CH2CH2OH, -NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl.
  • R 6 is cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexanyl, octahydropentalenyl, bicycle [l . l .
  • R 6 is cycloalkyl selected from Table A:
  • R 6 is heterocyclyl selected from Table B:
  • each optionally substituted with up to three substituents selected from F, -OH, oxo, -Ci-3 alkyl, -CH2OH, -CH2CH2OH, -C( 0)CH 2 OH, -CH2CH2CH2OH, - NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl.
  • L is a divalent cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • L is a divalent cycloalkyl selected from Table A:
  • L is a divalent heterocyclyl selected from Table B:
  • each heterocyclyl can be at any two CH and/or
  • substituents selected from F, -OH, oxo, -Ci-3 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl.
  • Y is -(CR a R b )i-, -(CR a R b )p-cycloalkyl-(CR a R b ) P -, -(CR a R b ) P -heterocyclyl-
  • R a , R b and R° are each independently H, F, -Ci-6 alkyl, or -Ci-6haloalkyl;
  • L is a divalent linker that can be connected in a chain in either direction, selected from absent, -(CR a R b )-, -(CR a R b ) 2 -, -(CR a R b ) P -cycloalkyl-(CR a R b ) P -, or - (CR a R b )p-heterocyclyl-(CR a R b ) P -, wherein cycloalkyl and heterocyclyl can be optionally further substituted with up to three substituents selected from F, -OH, oxo, -C1-3 alkyl, - CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl; and
  • R 7 is H, -Ci-6 alkyl, -Ci-6 haloalkyl, -C6-C12 aryl, C6-C12 aryl-Ci-C6 alkyl-, 5-12 membered heteroaryl, or 5-12 membered heteroaryl-Ci-C6 alkyl-, wherein -C6-C12 aryl, C6-Ci2 aryl-Ci-C6 alkyl-, 5-12 membered heteroaryl, and 5-12 membered heteroaryl- C1-C6 alkyl- can be optionally further substituted with up to three substituents selected from F, -OH, -C1-3 alkyl, -C1-3 haloalkyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or
  • X 1 is N; and X 2 is CH or N.
  • X 1 is N; and X 2 is CH.
  • X 1 is CH; and X 2 is CH or N.
  • X 1 is CH; and X 2 is CH.
  • X 1 is CH; and X 2 is CH.
  • X 1 is CH; and X 2 is N.
  • X 1 is CH or N; and X 2 is N.
  • R 3a and R 3b are each independently H or -C1-3 alkyl
  • R 5 is H
  • n is i .
  • R 1 is selected from hydrogen, fluoro, chloro, methyl, or cyano
  • R 2 is selected from hydrogen, fluoro, chloro, or cyano
  • R 3a and R 3b are each independently H, -C1-3 alkyl, or -C1-3 haloalkyl; or
  • R 3a and R 3b taken together with the carbon atom to which they are both attached, form a 3-7 membered ring, optionally containing up to two heteroatoms selected from O, S(0) x , or NR 11 , and wherein the 3-7 membered ring is optionally substituted with up to three substituents selected from hydroxyl, C1-3 alkoxy, oxo, cyano or
  • R a , R b and R° are each independently H, F, -Ci-6 alkyl, or -Ci-6 haloalkyl;
  • R 6 is H, -Ci-e alkyl, -Ci-e haloalkyl, -C3-12 cycloalkyl, -NR n R 7 , or a
  • L is a divalent linker that can be connected in a chain in either direction, selected from absent, -(CR a R b ) P -, -(CR a R b ) P -cycloalkyl-(CR a R b ) P -, or -(CR a R b ) P - heterocyclyl-(CR a R b ) P -, wherein cycloalkyl and heterocyclyl can be optionally further substituted with up to three substituents selected from F, -OH, oxo, C1-3 alkyl, CH2OH, CH2CH2OH, CH2CH2CH2OH, NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
  • C1-C6 alkyl- can be optionally further substituted with up to three substituents selected from F, -OH, -C1-3 alkyl, -C1-3 haloalkyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2OH, -
  • n is i, 2, or 3;
  • x is 0, 1, or 2.
  • the compound of the present disclosure relates to a compound having the structure of formula (A-I):
  • X 1 and X 2 are each independently CH or N;
  • R 1 is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF3, -OCH2CF3, -OCH2CHF2, -CF3, - CHF2, -CHO, -CH2OH, -CONH2, -CC Me, -CONHMe, -CONMe 2 , or cyano;
  • R 2 is selected from hydrogen, fluoro, chloro, methyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF3, -CF3, -CHF2, -CH2OH, -CONH2, -CONHMe, -CONMe2, or cyano;
  • R 3a and R 3b are each independently H, -Ci-6 alkyl, or -Ci-6haloalkyl; or
  • R 3a and R 3b taken together with the carbon atom to which they are both attached, form a 3-7 membered ring, optionally containing up to two heteroatoms selected from O, S(0) x , or NR 11 , or forms a 7-12 membered heterobicyclic ring which may be fused, bridged or spiro, and includes one to three heteroatoms selected from O, S(0) x , or NR 11 , and wherein the 3-7 membered ring and the 7-12 membered heterobicyclic ring are optionally substituted with up to three substituents selected from hydroxyl, -Ci-6alkoxy, -Ci-6 hydroxyalkyl, Ci-6 alkoxy-Ci-6 alkyl-, Ci-6 alkoxy-Ci-6 alkoxy-, C2-6 hydroxyalkoxy, oxo, thiono, cyano or halo;
  • Y is absent, -G-, -L-, -G-L-, or -L-G-;
  • R 5 is independently selected from H, -Ci-6 alkyl, halogen, -CN, -CD3, -CHF2,
  • R 6 is -Ci-e alkyl, -Ci-e haloalkyl, -C3-12 cycloalkyl, -NR n R 7 , a 5- , wherein -Ci-6 alkyl, -C 1-6 haloalkyl, -C3-
  • L is a divalent linker that can be connected in a chain in either direction, which is selected from absent, -(CR a R b ) P -, -(CR a R b )
  • R 7 is H, -Ci-6 alkyl, -Ci-6 haloalkyl, -C3-12 cycloalkyl, heterocyclyl, -C6-C12 aryl, C6-Ci2 aryl-Ci-C6 alkyl-, 5-12 membered heteroaryl, or 5-12 membered heteroaryl- C1-C6 alkyl-, wherein -C3-12 cycloalkyl, heterocyclyl, -C6-Ci2 aryl, C6-C12 aryl-Ci-C6 alkyl- , 5-12 membered heteroaryl, and 5-12 membered heteroaryl-Ci-C6 alkyl- can be optionally further substituted with up to three substituents selected from F, -OH, oxo, -Ci- 3 alkyl, -C1-3 haloalkyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2CH2
  • R n is H or -Ci-6 alkyl
  • R a , R b and R° are each independently H, F, -Ci-6 alkyl, or -C 1-6 haloalkyl;
  • n 1, 2, or 3;
  • p is independently 0, 1, or 2;
  • x is 0, 1, or 2.
  • Y is -L-G- or -G-L- and R 6 is 5- or 6-membered heterocyclyl which is optionally substituted with up to three substituents selected from F, -OH, oxo, -C1-3 alkyl, -C1-3 haloalkyl, -CH2OH, -CH2CH2OH, - CH2CH2CH2OH, or -NR n R n .
  • Y is -O-CH2- or -CH2-O-.
  • the pharmaceutical composition comprises a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises at least one additional therapeutically active agent.
  • the additional therapeutically active agent is an anticancer agent.
  • a method for modulating cyclin-dependent kinase comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • the modulating CDK is inhibiting CDK.
  • CDK is CDK4, CDK6, or CDK4/6.
  • a method for treating, ameliorating, or preventing a condition which responds to modulation of CDK comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • the condition is cancer.
  • CDK is CDK4, CDK6, or CDK4/6.
  • a method for treating a cell proliferative disorder comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • the cell proliferative disorder is cancer.
  • the cancer is breast cancer, colon cancer, ovarian cancer, non-small cell lung cancer, or Rb-positive glioblastoma.
  • the method further comprises administering at least one additional therapeutically active agent.
  • the additional therapeutically active agent is an anticancer agent.
  • a method for preparing a medicament comprising a therapeutically effective amount of a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • the method relates to preparing a medicament for treating a condition which responds to modulation of cyclin-dependent kinase, comprising a therapeutically effective amount of a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • CDK is CDK4, CDK6, or CDK4/6.
  • a method for protecting a subject from effects of ionizing radiation or chemotherapeutic agents comprising administering a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • the effects of ionizing radiation or chemotherapeutic agents are acute effects or chronic toxic effects in replication-dependent hematopoietic stem cells or progenitor cells (HSPCs).
  • a method for protecting hematopoietic cell or progenitor cell populations in subject comprising administering a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof to a subject in need thereof.
  • the hematopoietic cell population is a replication-dependent hematopoietic stem cell population.
  • the subject is exposed to ionizing radiation or chemotherapeutic agents.
  • the method further comprising administration of a chemotherapeutic agent.
  • the chemotherapeutic agent is etoposide, carboplatin, topotecan, or a combination thereof. In a certain embodiment, the chemotherapeutic agent is administered within 24 hours or less of the administration of the compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. In one embodiment, a method is provided for protecting a subject from effects of ionizing radiation or chemotherapeutic agents, comprising administering a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof to a subject in need thereof.
  • Headings are included herein for reference and to aid in locating certain sections. Headings are not intended to limit the scope of the embodiments and concepts described in the sections under those headings, and those embodiments and concepts may have applicability in other sections throughout the entire disclosure.
  • a kinase inhibitor refers to one or more kinase inhibitors or at least one kinase inhibitor.
  • a kinase inhibitor refers to one or more kinase inhibitors or at least one kinase inhibitor.
  • the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein.
  • reference to “an inhibitor” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the inhibitors is present, unless the context clearly requires that there is one and only one of the inhibitors.
  • substantially refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
  • an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
  • the exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained.
  • the use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of action, characteristic, property, state, structure, item, or result.
  • compositions that is "substantially free of other active agents would either completely lack other active agents, or so nearly completely lack other active agents that the effect would be the same as if it completely lacked other active agents.
  • a composition that is "substantially free of an ingredient or element or another active agent may still contain such an item as long as there is no measurable effect thereof.
  • Amino refers to the -NH2 radical.
  • Halo "halide” or “halogen” refers to bromo, chloro, fluoro or iodo radical.
  • Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n- propyl, /-propyl, sec-propyl, «-butyl, /-butyl, sec-butyl, /-butyl, «-pentyl, i-amyl, «-hexyl, n- heptyl, «-octyl, «-nonyl, «-decyl, «-undecyl, and «-dodecyl.
  • an alkyl group can be optionally substituted.
  • the term "lower alkyl” refers to a C1-C6 alkyl, which can be linear or branched, for example including branched C3-C6 alkyl.
  • Alkylene refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twenty carbon atoms.
  • C1-C20 alkylene include methylene, ethylene, propylene, «-butylene, ethenylene, propenylene, «-butenylene, propynylene, «-butynylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.
  • An alkenyl group comprising up to 20 carbon atoms is a C2-C20 alkenyl
  • an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl
  • an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl
  • an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl.
  • a C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls.
  • a C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes alkenyls.
  • Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 3- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1- octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonen
  • alkyl group can be optionally substituted.
  • alkenylene or "alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twenty carbon atoms, and having one or more carbon-carbon double bonds.
  • C2-C20 alkenylene include ethene, propene, butene, and the like.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • an alkenylene chain can be optionally substituted.
  • Alkynyl or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twenty carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 20 are included.
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twenty carbon atoms, and having one or more carbon-carbon triple bonds.
  • C2-C20 alkynylene include ethynylene, propargylene and the like.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.
  • Alkoxy or "-O-alkyl” refers to a radical of the formula -ORa where Ra is an alkyl, alkenyl or alknyl radical as defined above containing one to twenty carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.
  • Alkylamino refers to a radical of the formula -NHRa or -NRaRa where each Ra is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
  • alkyl refers to a radical of the formula -Rb-Rc where Rb is an alkylene, alkenylene or alkynylene group as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.
  • Carbocyclyl refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl. Cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.
  • Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkynyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.
  • Cycloalkylalkyl or "-alkylcycloalkyl” refers to a radical of the formula -R -Rd where Rb is an alkylene, alkenylene, or alkynylene group as defined above and Rd is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one, two, three, four, five, six or more halo radicals, as defined above, e.g. , trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl,
  • haloalkyl group can be optionally substituted.
  • Haloalkenyl refers to an alkenyl radical, as defined above, that is substituted by one, two, three, four, five, six or more halo radicals, as defined above, e.g. , 1-fluoropropenyl, 1, 1- difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
  • Haloalkynyl refers to an alkynyl radical, as defined above, that is substituted by one, two, three, four, five, six or more halo radicals, as defined above, e.g. , 1-fluoropropynyl, 1- fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
  • Heterocyclyl refers to a stable 3- to 20-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below.
  • the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized; and the heterocyclyl radical can be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thio
  • hydroxyalkyl refers to an alkyl group that is substituted with one or more hydroxyl (-OH) groups. In certain embodiments, a hydroxyalkyl group is substituted with one, two, three, four, five or more -OH groups. A hydroxyalkyl group may optionally be substituted with one or more additional substituents as described herein.
  • hydrocarbyl refers to a monovalent hydrocarbon radical, whether aliphatic, partially or fully unsaturated, acyclic, cyclic or aromatic, or any combination of the preceding. In certain embodiments, a hydrocarbyl group has 1 to 40 or more, 1 to 30 or more, 1 to 20 or more, or 1 to 10 or more, carbon atoms.
  • hydrocarbylene refers to a divalent hydrocarbyl group. A hydrocarbyl or hydrocarbylene group may optionally be substituted with one or more substituents as described herein.
  • heterohydrocarbyl and heterohydrocarbylene groups include without limitation ethylene glycol and polyethylene glycol moieties, such as (-CH2CH20-) n H (a monovalent heterohydrocarbyl group) and (-CH2CH20-) n (a divalent heterohydrocarbylene group) where n is an integer from 1 to 12 or more, and propylene glycol and polypropylene glycol moieties, such as (-CH2CH2CH20-) n H and (-CH2CH(CH3)0-) n H (monovalent heterohydrocarbyl groups) and (-CH2CH2CH20-)n and (-CH2CH(CH3)0-)n (divalent heterohydrocarbylene groups) where n is an integer from 1 to 12 or more.
  • a heterohydrocarbyl or heterohydrocarbylene group may optionally be substituted with one or more substituents as described herein.
  • N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group can be optionally substituted.
  • Heteroaryl refers to a 5- to 20-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzoiuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[6][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzoiuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiopheny
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted.
  • Thioalkyl refers to a radical of the formula -SRa where Ra is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.
  • substituted means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, CI, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups;
  • a non-hydrogen atoms such
  • Substituted also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • a higher-order bond e.g., a double- or triple-bond
  • nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
  • a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
  • the invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products can result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabelled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • a "subject” can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like.
  • the terms "subject” and “patient” are used interchangeably herein in reference, e.g., to a mammalian subject, such as a human subject.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethane sulfonic acid, 2-hydroxyethan
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isoprop
  • a "pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g. , humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • composition refers to a substance (e.g., an active ingredient or an excipient) that is suitable for use in contact with the tissues and organs of a subject without excessive irritation, allergic response, immunogenecity and toxicity, is commensurate with a reasonable benefit/risk ratio, and is effective for its intended use.
  • a "pharmaceutically acceptable” carrier or excipient of a pharmaceutical composition is also compatible with the other ingredients of the composition.
  • an “effective amount” refers to a therapeutically effective amount or a prophylactically effective amount.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduced tumor size, increased life span, increased life expectancy, or sufficient to prevent development of, or to alleviate to some extent, or to abrogate, the disease or disorder being treated.
  • the term “therapeutically effective amount” also refers to an amount of a compound that is sufficient to elicit a biological or medical response of a cell, tissue, organ, system, animal or human which is sought by a researcher, veterinarian, medical doctor or clinician.
  • a therapeutically effective amount of a compound can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as smaller tumors, increased life span, increased life expectancy or prevention of the progression of prostate cancer to a castration-resistant form. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount can be less than a therapeutically effective amount.
  • Treating covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:
  • disease and “condition” can be used interchangeably or can be different in that the particular malady or condition cannot have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
  • the terms “prevent”, “preventing”, and “prevention” include delaying or precluding the onset of a disease or disorder, precluding a subject from acquiring a disease or disorder, and reducing a subject's risk of acquiring a disease or disorder.
  • the compounds of the invention, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (iS)- or, as (D)- or (L)- for amino acids.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • a "tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the present invention includes tautomers of any said compounds.
  • pharmaceutical combination refers to a single dosage form comprising at least two therapeutically active agents, or separate dosage forms comprising at least two therapeutically active agents together or separately for use in combination therapy.
  • one therapeutically active agent may be formulated into one dosage form and the other therapeutically active agent may be formulated into a single or different dosage forms.
  • one therapeutically active agent may be formulated into a solid oral dosage form whereas the second therapeutically active agent may be formulated into a solution dosage form for parenteral administration.
  • One embodiment of the present disclosure relates to novel aminopyrimidine compounds.
  • the present disclosure relates to compound of Formula (A) of
  • X 1 and X 2 are each independently CH or N;
  • R 1 is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF3, -OCH2CF3, -OCH2CHF2, -CF3, - CHF2, -CHO, -CH2OH, -CONH2, -CC Me, -CONHMe, -CONMe2, or cyano;
  • R 2 is selected from hydrogen, fluoro, chloro, methyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF3, -CF3, -CHF2, -CH2OH, -CONH2, -CONHMe, -CONMe2, or cyano;
  • R 3a and R 3b are each independently H, -Ci-6 alkyl, or -Ci-6haloalkyl; or
  • R 3a and R 3b taken together with the carbon atom to which they are both attached, form a 3-7 membered ring, optionally containing up to two heteroatoms selected from O, S(0) x , or NR 11 , or forms a 7-12 membered heterobicyclic ring which may be fused, bridged or spiro, and includes one to three heteroatoms selected from O, S(0)x, or NR 11 , and wherein the 3-7 membered ring and the 7-12 membered heterobicyclic ring are optionally substituted with up to three substituents selected from hydroxyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 alkoxy-Ci-6 alkyl, Ci-6 alkoxy-Ci-6 alkoxy, C2-6 hydroxyalkoxy, oxo, thiono, cyano or halo;
  • R 5 is independently selected from H, -Ci-6 alkyl, halogen, -CN, -CD3, -CHF2,
  • Y is -G-, -L-, -G-L-, -L-G-, -L-G-L-, -G-L-G-, -L-G-L-G-, or -G-L-G-L-;
  • R 6 is H, -Ci-6 alkyl, -Ci-e haloalkyl, -C3-12 cycloalkyl, -NR n R 7 , or a
  • R 7 is H, -Ci-6 alkyl, -Ci-6 haloalkyl, -C3-12 cycloalkyl, heterocyclyl, -C6-C12 aryl, C6-Ci2 aryl-Ci-C6 alkyl-, 5-12 membered heteroaryl, or 5-12 membered heteroaryl- C1-C6 alkyl-, wherein -C3-12 cycloalkyl, heterocyclyl, -C6-Ci2 aryl, C6-C12 aryl-Ci-C6 alkyl- , 5-12 membered heteroaryl, and 5-12 membered heteroaryl-Ci-C6 alkyl-can be optionally further substituted with up to three substituents independently selected from F, -OH, oxo, -C 1-3 alkyl, -C 1-3 haloalkyl, -CH2OH, -CH2CH2OH, -CH2CH2
  • R a and R b are each independently H, F, -Ci-6 alkyl, or -Ci-6 haloalkyl;
  • n is i, 2, or 3;
  • p is independently 0, 1, or 2;
  • x is 0, 1, or 2.
  • x is 0, 1, or 2.
  • Y-R 6 does not comprise the following sequence in either direction: -0-(CR a R b )-0-, -0-(CR a R b )-NR n -, -O- (CR a R b )-S(0)x-, -NR n -(CR a R b )-N, -NR n -(CR a R b )-S(0) x -, or -S(0) x -(CR a R b )-S(0) x -.
  • Y-R 6 is not:
  • R 20 is H, methyl, ethyl, isopropyl, cyclopropyl, or -CH2
  • R 21 is H, methyl, ethyl, -CH2CH2OH or -CH2CH2F;
  • R 22 is -NH2 or -NMe 2 ;
  • R 23 is H, methyl, or ethyl
  • R 24 is H or ethyl
  • R 25 is H or methyl.
  • Y-R 6 is not:
  • R 26 is H, methyl, or ethyl
  • R 27 is H or -OH.
  • R 1 is selected from hydrogen, fluoro, chloro, methyl, or cyano;
  • R 2 is selected from hydrogen, fluoro, or cyano
  • R 3a and R 3b taken together with the carbon atom to which they are both attached, form a 3-7 membered cycloalkyl ring, which are optionally substituted with up to three substituents selected from hydroxyl, -Ci-6 alkoxy, cyano, oxo, or halo;
  • R 5 is independently selected from H, -C1-3 alkyl, F, CI, -CN, or -CD3;
  • R a and R b are each independently H, F, -C1-3 alkyl, or -C1-3 haloalkyl;
  • R 7 is H, -Ci-3 alkyl, -C1-3 haloalkyl, -C6-C12 aryl, C6-C12 aryl-Ci-C6 alkyl-, 5-12 membered heteroaryl, or 5-12 membered heteroaryl-Ci-C6 alkyl-, wherein -C6-C12 aryl, C6-Ci2 aryl-Ci-C6 alkyl-, 5-12 membered heteroaryl, and 5-12 membered heteroaryl- C1-C6 alkyl- can be optionally further substituted with up to three substituents selected from F, -OH, -C1-3 alkyl, -C1-3 haloalkyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or
  • X 1 is N.
  • X 2 is CH.
  • X 2 is N.
  • X 1 is N and X 2 is CH or N. In other embodiments, X 1 is N and X 2 is CH. In one embodiment, X 1 is CH and X 2 is CH or N. In another embodiment, X 1 is CH and X 2 is CH. In some embodiments, X 1 is CH and X 2 is N. In other embodiments, X 1 is CH or N and X 2 is N.
  • R 1 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, - OCF3, -OCH2CF3, -OCH2CHF2, -CF3, -CHF2, -CHO, -CH2OH, or cyano.
  • R 1 is hydrogen, fluoro, chloro, bromo, methyl, methoxy, -OCF3, -CF3, -CHF2, or cyano.
  • R 1 is hydrogen, fluoro, chloro, methyl, or cyano.
  • R 1 is hydrogen, fluoro, chloro, or methyl.
  • R 1 is fluoro or chloro.
  • R 3a and R 3b are each independently H, -Ci-6 alkyl, or -Ci-6 haloalkyl. In another embodiment, R 3a and R 3b are each independently H, -C1-3 alkyl, or -C1-3 haloalkyl. In some embodiments, R 3a and R 3b are each independently H, methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3a and R 3b are each independently H, methyl, or ethyl. In other embodiments, R 3a and R 3b are each independently H or methyl. In one embodiment, R 3a and R 3b are each H. In other embodiments, R 3a and R 3b are each methyl.
  • R 3a and R 3b together forms a 3-7 membered cycloalkyl ring, optionally substituted with up to three substituents selected from hydroxyl, Ci-6 alkoxy, cyano, oxo, or halo.
  • R 6 is optionally substituted with up to three substituents independently selected from -Ci-6 alkyl, -Ci-6 haloalkyl, F, -OH, oxo, -CH2OH, -CH2CH2OH, -
  • R 6 is substituted
  • R 6 is substituted with -NR n R n ; wherein R n is
  • R 6 is substituted with -NR n R n ; wherein R n is each methyl.
  • R 6 is cycloalkyl selected form Table A, wherein the connectivity of each cycloalkyl can be at any one of CH or NH by replacing a hydrogen to form a bond to the heteroaryl containing X 2 .
  • R 6 is heterocyclyl selected from Table B,
  • each heterocyclyl can be at any two CH and/or NH on the heterocyclyl by replacing a hydrogen for a bond
  • each optionally substituted with up to three substituents selected from F, -OH, oxo, -Ci-3 alkyl, -CH2OH, -CH2CH2OH, -C( 0)CH 2 OH, -CH2CH2CH2OH, - NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl.
  • Y selected from -G-, -L-, -G-L-, or -L-G-.
  • Y is -G-.
  • Y is -L-. In one embodiment of the compounds of formula (A) or formula (B), Y is -L-, wherein L is a divalent linker selected from -(CR a R b ) P -, -(CR a R b ) P -cycloalkyl-(CR a R b ) P -, or -(CR a R b ) P - heterocyclyl-(CR a R b ) P -, wherein cycloalkyl and heterocyclyl can be optionally further substituted with up to three substituents selected from F, -OH, oxo, -C1-3 alkyl, -C1-3 haloalkyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -NR n R n , aziridinyl, azetidinyl, pyr
  • Y is -L-, wherein L is a divalent linker selected from -(CR a R b ) P -, -(CR a R b ) P -cycloalkyl-(CR a R b )p-, or -(CR a R b ) P -heterocyclyl-(CR a R b ) P -.
  • Y is -L-, wherein L is a divalent linker - (CR a R b ) P -.
  • Y is -L-, wherein L is a divalent linker -CH2-.
  • Y-R 6 is
  • L is a divalent cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • L is a divalent cycloalkyl selected form Table A, wherein each cycloalkyl can be attached at any two CH by replacing a hydrogen for a bond.
  • L is divalent heterocyclyl selected from Table B,
  • each heterocyclyl can be at any two CH and/or
  • R a is H, -C1-3 alkyl, or -C1-3 haloalkyl. In another embodiment, R a is H or -C1-3 alkyl. In one embodiment, R a is H.
  • R b is H, -C1-3 alkyl, or -C1-3 haloalkyl. In another embodiment, R b is H or -C1-3 alkyl. In one embodiment, R b is H.
  • R n is each H, - Ci-6 alkyl, or -C 1-6 haloalkyl. In another embodiment, R n is each H or -C1-3 alkyl. In one embodiment, R n is each H or methyl. In one embodiment, R n is each methyl. [298] In one embodiment of the compounds of formula (A) or formula (B), n is 1. In one embodiment of the compounds of formula (A) or formula (B), n is 2. In one embodiment of the compounds of formula (A) or formula (B), n is 3.
  • p is 1 or 2. In one embodiment of the compounds of formula (A) or formula (B), p is 1.
  • Y is -(CR a R b )i-, -(CR a R b )p-cycloalkyl-(CR a R b ) P -, -(CR a R b ) P -heterocyclyl- (CR a R b ) P -, -G-L-, -L-G-, -L-G-L-, -G-L-G-, -L-G-L-G-, or -G-L-G-L-;
  • R a , R b and R° are each independently H, F, -Ci-6 alkyl, or -Ci-6haloalkyl;
  • R 7 is H, -Ci-6 alkyl, -Ci-6 haloalkyl, -C6-C12 aryl, C6-C12 aryl-Ci-C6 alkyl-, 5-12 membered heteroaryl, or 5-12 membered heteroaryl-Ci-C6 alkyl-, wherein -C6-C12 aryl, C6-Ci2 aryl-Ci-C6 alkyl-, 5-12 membered heteroaryl, and 5-12 membered heteroaryl- C1-C6 alkyl- can be optionally further substituted with up to three substituents selected from F, -OH, -C1-3 alkyl, -C1-3 haloalkyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
  • the compound has the structure of formula (C):
  • R 1 is selected from hydrogen, fluoro, chloro, methyl, or cyano
  • R 2 is selected from hydrogen, fluoro, chloro, or cyano
  • R 3a and R 3b are each independently H, -C1-3 alkyl, or -C1-3 haloalkyl; or
  • R 3a and R 3b taken together with the carbon atom to which they are both attached, form a 3-7 membered ring, optionally containing up to two heteroatoms selected from O, S(0) x , or NR 11 , and wherein the 3-7 membered ring is optionally substituted with up to three substituents selected from hydroxyl, -C1-3 alkoxy, oxo, cyano or F;
  • R a , R b and R° are each independently H, F, -Ci-6 alkyl, or -C 1-6 haloalkyl;
  • R 6 is H, -Ci-6 alkyl, -Ci-e haloalkyl, -C3-12 cycloalkyl, -NR n R 7 , or a
  • L is a divalent linker that can be connected in a chain in either direction, selected from absent, -(CR a R b ) P -, -(CR a R b ) P -cycloalkyl-(CR a R b ) P -, -(CR a R b ) P - heterocyclyl-(CR a R b ) P -, wherein cycloalkyl and heterocyclyl can be optionally further substituted with up to three substituents selected from F, -OH, oxo, -C1-3 alkyl, -CH2OH, - CH2CH2OH, -CH2CH2CH2OH, -NR n R n , aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
  • C1-C6 alkyl- can be optionally further substituted with up to three substituents selected from F, -OH, -C1-3 alkyl, -C1-3 haloalkyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, --CH2CH2CH2OH, -
  • NR n R n aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
  • p is independently 0, 1, or 2;
  • x is 0, 1, or 2.
  • R 3a and R 3b are each independently H or -C1-3 alkyl; and Y is -O-CH2- or -CH2-O-.
  • the compound of the present disclosure has the structure of formula (B).
  • X 2 is CH
  • R 3a and R 3b are each independently H or -C1-3 alkyl
  • Y is selected from -CH2-, -O-CH2-, or -CH2-O-; and [336] n is i .
  • the compound of the present disclosure relates to a compound having the structure of formula (A-I):
  • X 1 and X 2 are each independently CH or N;
  • R 1 is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF3, -OCH2CF3, -OCH2CHF2, -CF3, - CHF2, -CHO, -CH2OH, -CONH2, -CC Me, -CONHMe, -CONMe 2 , or cyano;
  • R 2 is selected from hydrogen, fluoro, chloro, methyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF3, -CF3, -CHF2, -CH2OH, -CONH2, -CONHMe, -CONMe2, or cyano;
  • R 3a and R 3b are each independently H, -Ci-6 alkyl, or -Ci-6haloalkyl; or
  • R 3a and R 3b taken together with the carbon atom to which they are both attached, form a 3-7 membered ring, optionally containing up to two heteroatoms selected from O, S(0) x , or NR 11 , or forms a 7-12 membered heterobicyclic ring which may be fused, bridged or spiro, and includes one to three heteroatoms selected from O, S(0) x , or NR 11 , and wherein the 3-7 membered ring and the 7-12 membered heterobicyclic ring are optionally substituted with up to three substituents selected from hydroxyl, -Ci-6alkoxy, Ci-6hydroxyalkyl, Ci-6 alkoxy-C 1-6 alkyl, Ci-6 alkoxy-Ci-6 alkoxy, C2-6 hydroxyalkoxy, oxo, thiono, cyano or halo;
  • Y is absent, -G-, -L-, -G-L-, or -L-G-;
  • R 5 is independently selected from H, Ci-6 alkyl, halogen, -CN, -CD3, -CHF2, or
  • R 6 is -Ci-e alkyl, -Ci-e haloalkyl, -C3-12 cycloalkyl, -NR n R 7 , a 5-
  • R 7 is H, -Ci-6 alkyl, -Ci-6 haloalkyl, -C3-12 cycloalkyl, heterocyclyl, -C6-C12 aryl, C6-Ci2 aryl-Ci-C6 alkyl-, 5-12 membered heteroaryl, or 5-12 membered heteroaryl- C1-C6 alkyl-, wherein -C3-12 cycloalkyl, heterocyclyl, -C6-Ci2 aryl, C6-C12 aryl-Ci-C6 alkyl- , 5-12 membered heteroaryl, and 5-12 membered heteroaryl-Ci-C6 alkyl- can be optionally further substituted with up to three substituents selected from F, -OH, oxo, -Ci- 3 alkyl, -C1-3 haloalkyl, -CH2OH, -CH2CH2OH, -CH2CH2CH
  • R n is H or Ci-6 alkyl
  • R a , R b and R° are each independently H, F, -Ci-6 alkyl, or -C 1-6 haloalkyl;
  • n is i, 2, or 3;
  • p is independently 0, 1, or 2;
  • x is 0, 1, or 2.
  • Y is absent and R 6 is a 5- membered heterocyclyl, optionally substituted with -NR n R n .
  • Y is -G- and R 6 is 5- membered heterocyclyl, optionally substituted with -NR n R n .
  • R 20 is -CH2OH, -CH2CH2OH, -
  • Y is -L-G- or -G-L-
  • R 3a and R 3b are each
  • formula (A-I) is a subgenus of formula (A). Any embodiments discussed for the compounds of formula (A) can be applied for compounds of formula (A-I).
  • Y is -O-CH2- or -CH2-O-.
  • R 1 is hydrogen, fluoro, chloro, methyl, or cyano. In some embodiments, R 1 is fluoro.
  • R 2 is hydrogen, fluoro, chloro, or cyano. In some embodiments, R 2 is fluoro.
  • R 3a and R 3b are each independently H or -C1-3 alkyl. In one embodiment, R 3a and R 3b are each independently H or methyl. In some embodiments, R 3a and R 3b are each H. In other embodiments, R 3a and R 3b are each methyl.
  • the compound of the present disclosure excludes compounds in
  • the compound of the present disclosure excludes compounds in
  • the compounds of the present disclosure excludes the compounds exemplified in WO2017/071516 and WO 2016/173505.
  • One embodiment of the present disclosure relates to novel aminopyrimidine compounds.
  • Xi, X2, and X7 is selected from N, C, or CH;
  • X2 is a N
  • X4 is selected from NH, NR5 or CH2
  • X5 is selected from CH2 or O;
  • X 3 is selected from N or CH; [387] ring A is an aromatic ring;
  • R3 is selected from acyl or optionally substituted alkyl
  • Xs is optionally substituted with one to four substituents each independently selected from: C1-C3 alkyl optionally substituted with one or two substituents each independently selected from hydroxyl or -S-(Ci-C3 alkyl); -CD3; halo; oxo; C1-C3 haloalkyl; hydroxyl; NH2; dimethylamino; benzyl; or -C(0)-(Ci-C3 alkyl) optionally substituted with one or two substituents each independently selected from: -SCH3, -NHC(0)CH3, -S(0)2-(Ci-C4 alkyl), or -C(0)-pyrrolidinyl;
  • Ri and R2 is selected from H, alkyl, substituted alkyl; or Ri and R2 together with the carbon atom to which they are attached to can form a 3-8 membered optionally substituted cycloalkyl or a 3-8 membered optionally substituted heterocycloalkyl containing one or more of O, N, S, SO, or S0 2 ;
  • R4 is selected from H, CN, alkyl, substituted alkyl or halogen;
  • R5 is selected from H, alkyl, substituted alkyl
  • Re and Rs are each independently selected from H, CN, C1-C6 alkyl, substituted C1-C6 alkyl, CI, F, or Br.
  • Ring A refers to the 5-membered ring in formula (I) formed by Xi, X2, X3, and the two adjacent carbon atoms.
  • the dotted circle in Ring A demonstrates that the ring is aromatic.
  • ring A of formula (I) is a pyrazole ring or an imidazole ring.
  • Xi is C; and X2 and X3 are each N in formula (I).
  • X2 is C; and Xi and X3 are each N in in formula (I).
  • the compound of formula (I) has the structure of formula (Ij) or Ik):
  • X7 of formula (I) is N or CH. In one embodiment, X7 is CH.
  • Xs of formula (I) is . In one embodiment, Xs of formula (I)
  • R3 is selected from methyl, ethyl, propyl, isopropyl, butyl, -C(0)CH3, - H 2 CH 3 , -C(0)CH 2 OH, or -C(0)CH 2 CH 2 OH.
  • X 8 formula (Ij) is
  • R3 is -C(0)CH 2 OH.
  • X of formula (Ik) is and R3 is methyl, ethyl, propyl, or isopropyl.
  • Ri of formula (I) is H or C1-C6 alkyl. In another embodiment, Ri is methyl, ethyl, propyl, or butyl. In another embodiment, Ri is methyl.
  • R2 of formula (I) is H or C1-C6 alkyl. In another embodiment, R2 is methyl, ethyl, propyl, or butyl. In another embodiment, R2 is methyl.
  • Ri and R2 of formula (I) are each methyl.
  • Ri and R2 of formula (I) together with the carbon atom to which they are attached to can form a 3-6 membered optionally substituted cycloalkyl or a 3-6 membered optionally substituted heterocycloalkyl containing one or more of O, N, S, SO, or
  • R4 of formula (I) is H, CN, or halogen. In one embodiment, R4 is H.
  • Re of formula (I) is H, CN, C1-C6 alkyl, CI, F, or Br. In another embodiment, Re is H, CI, F, or Br. In one embodiment, R6 is H, CI, or F. In some embodiments, Re is F.
  • Re and Rs of formula (I) are each F.
  • a compound of formula (I) has the structure of formula (la):
  • Xi and X2 is selected from N, C, or CH;
  • X 4 and X5 when X 2 is C or CH, X 4 and X5 is selected from O, NH, NR5 or CH 2 , provided that X4 and X5 cannot be both O;
  • X 3 is selected from N or CH;
  • ring A is an aromatic ring
  • Xs is selected from: R 3 .
  • R3 is selected from acyl or optionally substituted alkyl
  • Xs is optionally substituted with one to four substituents each independently selected from: C1-C3 alkyl optionally substituted with one or two substituents each independently selected from hydroxyl or -S-(Ci-C3 alkyl); -CD3; halo; oxo; C1-C3 haloalkyl; hydroxyl; NH2; dimethylamino; benzyl; or -C(0)-(Ci-C3 alkyl) optionally substituted with one or two substituents each independently selected from: -SCH3, -NHC(0)CH3, -S(0)2-(Ci-C4 alkyl), or -C(0)-pyrrolidinyl;
  • R4 is selected from H, CN, alkyl, substituted alkyl or halogen;
  • Re and Rs are each independently selected from H, CN, C1-C6 alkyl, substituted C1-C6 alkyl, CI, F, or Br. [429] In one embodiment, various embodiments as described for formula (I) also can be applied to formula (la).
  • Re of formula (la) is selected from H, CN, CI, F, or Br. In one embodiment, Re of formula (la) is selected from H, CN, CI, or F.
  • Rs of formula (la) is selected from H, CN, CI, F, or Br. In one embodiment, Rs of formula (la) is selected from H, CN, CI, or F.
  • a compound of formula (I) has the structure of formula (Ic):
  • Xi and Xi is selected from N, C, or CH;
  • X3 is selected from N;
  • X4 and X5 are each CH2;
  • R3 is selected from acyl or optionally substituted alkyl
  • Ri, R2, and R5 are each selected from H, alkyl, substituted alkyl;
  • R4 is selected from H, CN, C1-C6 alkyl, or halogen
  • Re and Rs are each independently selected from H, CN, or F.
  • formula (I) [444] in one embodiment, various embodiments as described for formula (I) also can be applied to formulae (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), and (Ik).
  • One embodiment of the present disclosure relates to novel aminopyrimidine compounds.
  • Xi and X2 are each selected from N, C, or CH; wherein
  • X 4 and X5 is selected from O, NH, NR5 or CH 2 , provided that X4 and X5 cannot be both O;
  • X2 is a N
  • X4 is selected from NH, NR5 or CH2
  • X5 is selected from CH2 or
  • X3 is selected from N or CH;
  • ring A is an aromatic ring
  • Ri and R2 is selected from H, alkyl, substituted alkyl; or Ri and R2 together with the carbon atom to which they are attached to can form a 3-8 membered optionally substituted cycloalkyl or a 3-8 membered optionally substituted heterocycloalkyl containing one or more of O, N, S, SO, or S0 2 ;
  • Re and Rs are each independently selected from H, CN, C1-C6 alkyl, substituted C1-C6 alkyl, CI, F, or Br;
  • Ri4 is selected from -H, -OH, or an optionally substituted -(C1-C6 alkyl), wherein the optional substituent for -(C1-C6 alkyl) is selected from 1-3 substituents from -OH, halo, or -O- (Ci-Ce alkyl);
  • Ri5 is selected from -H, -OH, or an optionally substituted -(C1-C6 alkyl), wherein the optional substituent for -(C1-C6 alkyl) is selected from 1-3 substituents from -OH, halo, or -O- (Ci-Ce alkyl);
  • Ri8 is -H or an optionally substituted -(C1-C6 alkyl), wherein the optional substituent for -(C1-C6 alkyl) is selected from 1-3 substituents from -OH, halo, or -0-(Ci-C6 alkyl);
  • Ri9 is -H or an optionally substituted -(C1-C6 alkyl), wherein the optional substituent for -(C1-C6 alkyl) is selected from 1-3 substituents from -OH, halo, or -0-(Ci-C6 alkyl);
  • R and R" are each independently selected from -H or optionally substituted -(C1-C4 alkyl), wherein the optional substituent for -(C1-C4 alkyl) is selected from 1-3 substituents from -OH or - F.
  • Ring A refers to the 5-membered ring in formula (II) formed by Xi, X2, X3, and the two adjacent carbon atoms.
  • the dotted circle in Ring A demonstrates that the ring is aromatic.
  • ring A of formula (II) is a pyrazole ring or an imidazole ring.
  • Xi is C; and X2 and X3 are each N in formula (II).
  • X2 is C; and Xi and X3 are each N in formula (II).
  • the compound of formula (II) has the structure of formula (Ilj) or
  • the compound of formula (II) has the structure of formula (lid),
  • Ri of formula (II) is H or C1-C6 alkyl. In anotlier embodiment, Ri is methyl, ethyl, propyl, or butyl. In another embodiment, Ri is methyl.
  • R2 of formula (II) is H or C1-C6 alkyl. In another embodiment, R2 is methyl, ethyl, propyl, or butyl. In another embodiment, R2 is methyl.
  • Ri and R2 of formula (II) are each methyl.
  • Ri and R2 of formula (II) together with the carbon atom to which they are attached to can form a 3-6 membered optionally substituted cycloalkyl or a 3-6 membered optionally substituted heterocycloalkyl containing one or more of O, N, S, SO, or
  • R6 of formula (II) is H, CN, C1-C6 alkyl, CI, F, or Br.
  • Re is H, CI, F, or Br.
  • Re is H, CN, CI, F, or Br.
  • Re is H, CN, CI, or F.
  • Re is F.
  • Rs of formula (II) is H, CN, C1-C6 alkyl, CI, F, or Br. In another embodiment, Rs is H, CI, F, or Br. In one embodiment, Rs is H, CN, CI, F, or Br. In one embodiment, Rs is H, CN, CI, or F. In some embodiments, Rs is F.
  • Re and Rs of formula (II) are each F.
  • ring Rio of formula (II) is formula B:
  • Rio of formula (II) is formula B where R12, R13, R14, R15, Ri6, R17, Ri8, and Ri9 are each H.
  • Rio of formula (He) is formula B where R12, R13, R14, R15, Ri6, Rn, Ri8, and Ri9 are each H and R11 is ethyl.
  • ring Rio of formula (II) is formula C:
  • Rio of formula (II) is formula C where R12, R13, R14, R15, Ri6, R17, Ri8, and Ri9 are each H.
  • Rio of formula (II) is formula D where R12, R13, R14, R15, Ri6, R17, Ri8, and Ri9 are each H.
  • Rio of formula (II) is formula E where R12, R13, R14, R15, Ri6, Rn, Ri8, and Ri9 are each H.
  • Ri6 and Rn relating to formula (II) are each independently selected from H, or an optionally substituted -(C1-C6 alkyl), wherein the optional substituent for -(Ci- C6 alkyl) is selected from 1-3 substituents from -OH, halo, or -0-(Ci-C6 alkyl).
  • Ris relating to formula (II) is -H or an optionally substituted -(Ci- C6 alkyl), wherein the optional substituent for -(C1-C6 alkyl) is selected from 1-3 substituents from -OH, halo, or -0-(Ci-C6 alkyl).
  • R19 relating to formula (II) is -H or an optionally substituted -(Ci- C6 alkyl), wherein the optional substituent for -(C1-C6 alkyl) is selected from 1-3 substituents from -OH, halo, or -0-(Ci-C6 alkyl).
  • Ris and R19 relating to formula (II) is each independently selected from -H or an optionally substituted -(C1-C6 alkyl), wherein the optional substituent for -(Ci- C6 alkyl) is selected from 1-3 substituents from -OH, halo, or -0-(Ci-C6 alkyl).
  • a compound of formula (II) is selected from:
  • the compound of formula (II) excludes
  • formula (II) also can be applied to formulae (lid), (He), (Id), (Ie), (If), (Ig), (Eh), (Ii), (Ij), and (Ik).
  • the present disclosure also includes method of using a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, and/or a pharmaceutical composition comprising one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, as described herein.
  • the present disclosure provides method of modulating cyclin-dependent kinase (CDK) by contacting one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, with a cell, an organ, or a subject, in need thereof.
  • a method of modulating CDK comprises administering to a subject, a therapeutically effective amount of one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • the subject is a mammal including human.
  • the method for modulating CDK as described herein is for inhibiting CDK.
  • CDK is CDK4.
  • CDK is CDK6.
  • CDK is CDK4/6.
  • a method of treating, ameliorating, or preventing a condition which is responds to modulation of CDK comprises administering to a subject, a therapeutically effective amount of one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • the subject is a mammal including human.
  • the condition which responds to modulation of CDK is a condition which responds to inhibition of CDK.
  • CDK is CDK4.
  • CDK is CDK6.
  • CDK is CDK4/6.
  • the condition is cancer.
  • a method of treating, ameliorating, or preventing a condition which is responds to modulation of CDK can be reducing or inhibiting cancer cell growth or tumor growth.
  • CDK is CDK4.
  • CDK is CDK6.
  • CDK is CDK4/6.
  • the present disclosure provides a method of treating cell proliferative disorder comprising contacting one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, with a cell, an organ, or a subject, in need thereof.
  • a method of treating cell proliferative disorder comprises administering to a subject, one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • the subject is a mammal including human.
  • the cell proliferative disorder is cancer.
  • the present disclosure describes a method of treating cancer comprising administration of one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • Non-limiting examples of cancer applicable by method of treatment as disclosed herein includes: Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma, Lymphoma, Anal Cancer, Appendix Cancer, Astrocytomas, Childhood Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Bile Duct Cancer, Extrahepatic Bladder Cancer, Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Stem Glioma, Brain Tumors, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma, Ependymoma, Bronchial Tumors, Burkitt Lymphoma (Non-Hodgkin Lymphoma), Carcinoid Tumor, Gastrointestinal
  • the present disclosure relates to a method of treating cancer comprising administering one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, to a subject in need thereof.
  • cancer is breast cancer, colon cancer, ovarian cancer, lung cancer, or glioblastoma.
  • the lung cancer is a non-small cell lung cancer.
  • the glioblastoma is a Rb-positive glioblastoma.
  • the compound is administered in a therapeutically effective amount.
  • the present disclosure relates to a method of protecting a subject from effects of ionizing radiation or chemotherapeutic agent comprising administering one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, to a subject in need thereof.
  • the effects of ionizing radiation or chemotherapeutic agents are acute effects and/or chronic toxic effects.
  • the acute and/or chronic toxic effects are in hematopoietic stem cells and/or progenitor cells (HSPCs).
  • the hematopoietic stem cells are replication-dependent hematopoietic stem cells.
  • the method of protecting a subject from effects of ionizing radiation or chemotherapeutic agent further comprises administering another chemotherapeutic agent in combination with the compound of the present disclosure.
  • the chemotherapeutic agent administered in combination with the compound of the present disclosure is etoposide, carboplatin, topotecan, or a combination thereof.
  • the administration of the combination of the chemotherapeutic agent administered in combination with the compound of the present disclosure is provided within 24 hours or less. That is, the chemotherapeutic agent can be provided within 24 hours or less after the administration of the compound of the present disclosure.
  • the compound of the present disclosure and/or the chemotherapeutic agent is administered in a therapeutically effective amount.
  • the present disclosure relates to a method of reducing or limiting the effect of DNA-damaging ionizing radiation or chemotherapeutic agent on hematopoietic stem cells and/or progenitor cells (HSPCs), comprising administering one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, to a subject in need thereof.
  • the hematopoietic stem cells are replication-dependent hematopoietic stem cells.
  • the method of reducing or limiting the effect of DNA-damaging ionizing radiation or chemotherapeutic agent on HSPCs further comprises administering another chemotherapeutic agent in combination with the compound of the present disclosure.
  • the chemotherapeutic agent administered in combination with the compound of the present disclosure is etoposide, carboplatin, topotecan, or a combination thereof.
  • the administration of the combination of the chemotherapeutic agent administered in combination with the compound of the present disclosure is provided within 24 hours or less. That is, the chemotherapeutic agent can be provided within 24 hours or less after the administration of the compound of the present disclosure.
  • the compound of the present disclosure and/or the chemotherapeutic agent is administered in a therapeutically effective amount
  • the present disclosure relates to a method of protecting hematopoietic cell and/or progenitor cell populations in subject, comprising administering one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, to a subject in need thereof.
  • the subject is exposed to ionizing radiation or chemotherapeutic agents.
  • the hematopoietic stem cells are replication-dependent hematopoietic stem cells.
  • the method of protecting hematopoietic cell and/or progenitor cell populations in a subject further comprises administering another chemotherapeutic agent in combination with the compound of the present disclosure.
  • the chemotherapeutic agent administered in combination with the compound of the present disclosure is etoposide, carboplatin, topotecan, or a combination thereof.
  • the administration of the combination of the chemotherapeutic agent administered in combination with the compound of the present disclosure is provided within 24 hours or less. That is, the chemotherapeutic agent can be provided within 24 hours or less after the administration of the compound of the present disclosure.
  • the compound of the present disclosure and/or the chemotherapeutic agent is administered in a therapeutically effective amount
  • the present disclosure relates to a method of promoting the recovery of a hematopoietic cell and/or progenitor cell population in subject, comprising administering one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, to a subject in need thereof.
  • the subject is exposed to ionizing radiation or chemotherapeutic agents.
  • the hematopoietic stem cells are replication- dependent hematopoietic stem cells.
  • the method of promoting the recovery of a hematopoietic cell and/or progenitor cell population in subject further comprises administering another chemotherapeutic agent in combination with the compound of the present disclosure.
  • the chemotherapeutic agent administered in combination with the compound of the present disclosure is etoposide, carboplatin, topotecan, or a combination thereof.
  • the administration of the combination of the chemotherapeutic agent administered in combination with the compound of the present disclosure is provided within 24 hours or less. That is, the chemotherapeutic agent can be provided within 24 hours or less after the administration of the compound of the present disclosure.
  • the compound of the present disclosure and/or the chemotherapeutic agent is administered in a therapeutically effective amount
  • any one of methods as disclosed herein can comprise additional therapeutically active agents (in addition to the one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof).
  • the additional therapeutically active agent is an anticancer agent.
  • the additional therapeutically active agent is administered in a therapeutically effective amount.
  • the present disclosure also includes pharmaceutical compositions comprising one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, in a pharmaceutical composition as described herein modulates cyclin-dependent kinase (CDK) such as CDK4/6.
  • CDK cyclin-dependent kinase
  • one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, in a pharmaceutical composition as described herein can be useful in a method to treat, ameliorate or prevent a condition, which responds to inhibition of CDK (e.g., CDK4/6) or in a method of treating cell proliferative disorder.
  • CDK e.g., CDK4/6
  • a pharmaceutical composition as described herein, comprising one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, further comprises one or more additional therapeutically active agents.
  • one or more additional therapeutically active agents are selected from anticancer agents.
  • Anticancer agents used in combination with the compounds of the present application may include agents selected from any of the classes known to those of ordinary skill in the art, including, for example, alkylating agents, anti-metabolites, plant alkaloids and terpenoids (e.g., taxanes), topoisomerase inhibitors, anti-tumor antibiotics, kinase inhibitors, hormonal therapies, molecular targeted agents, and the like.
  • an anticancer agent is an alkylating agent, an anti-metabolite, a vinca alkaloid, a taxane, a topoisomerase inhibitor, an anti-tumor antibiotic, a tyrosine kinase inhibitor, an immunosuppressive macrolide, an Akt inhibitor, an HDAC inhibitor an Hsp90 inhibitor, an mTOR inhibitor, a PI3K/mTOR inhibitor, a PI3K inhibitor, CHK (checkpoint kinase) inhibitor, PARP (poly (DP-ribose)polymerase) inhibitors, and the like.
  • Alkylating agents include (a) alkylating -like platinum-based chemotherapeutic agents such as cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, and (SP-4-3)-(cis)- amminedichloro-[2-methylpyridine] platinum(II); (b) alkyl sulfonates such as busulfan; (c) ethyleneimine and methylmelamine derivatives such as altretamine and thiotepa; (d) nitrogen mustards such as chlorambucil, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, trofosamide, prednimustine, melphalan, and uramustine; (e) nitrosoureas such as carmustine, lomustine, fotemustine, nimustine, ranimustine and streptozocin; (f) triazene
  • Anti-metabolites also include thymidylate synthase inhibitors, such as fluorouracil, raltitrexed, capecitabine, floxuridine and pemetrexed; and ribonucleotide reductase inhibitors such as claribine, clofarabine and fludarabine.
  • thymidylate synthase inhibitors such as fluorouracil, raltitrexed, capecitabine, floxuridine and pemetrexed
  • ribonucleotide reductase inhibitors such as claribine, clofarabine and fludarabine.
  • Plant alkaloid and terpenoid derived agents include mitotic inhibitors such as the vinca alkaloids vinblastine, vincristine, vindesine, and vinorelbine; and microtubule polymer stabilizers such as the taxanes, including, but not limited to paclitaxel, docetaxel, larotaxel, ortataxel, and tesetaxel.
  • Topoisomerase inhibitors include topoisomerase I inhibitors such as camptothecin, topotecan, irinotecan, rubitecan, and belotecan; and topoisomerase II inhibitors such as etoposide, teniposide, and amsacrine.
  • Anti -tumor antibiotics include (a) anthracyclines such as daunorubicin (including liposomal daunorubicin), doxorubicin (including liposomal doxorubicin), epirubicin, idarubicin, and valrubicin; (b) streptomyces-related agents such as bleomycin, actinomycin, mithramycin, mitomycin, porfiromycin; and (c) anthracenediones, such as mitoxantrone and pixantrone.
  • anthracyclines such as daunorubicin (including liposomal daunorubicin), doxorubicin (including liposomal doxorubicin), epirubicin, idarubicin, and valrubicin
  • streptomyces-related agents such as bleomycin, actinomycin, mithramycin, mitomycin, porfiromycin
  • anthracenediones such
  • Anthracyclines have three mechanisms of action: intercalating between base pairs of the DNA/RNA strand; inhibiting topoiosomerase II enzyme; and creating iron-mediated free oxygen radicals that damage the DNA and cell membranes.
  • Anthracyclines are generally characterized as topoisomerase II inhibitors.
  • Hormonal therapies include (a) androgens such as fluoxymesterone and testolactone; (b) antiandrogens such as bicalutamide, cyproterone, flutamide, and nilutamide; (c) aromatase inhibitors such as aminoglutethimide, anastrozole, exemestane, formestane, and letrozole; (d) corticosteroids such as dexamethasone and prednisone; (e) estrogens such as diethylstilbestrol; (f) antiestrogens such as fulvestrant, raloxifene, tamoxifen, and toremifine; (g) LHRH agonists and antagonists such as buserelin, goserelin, leuprolide, and triptorelin; (h) progestins such as medroxyprogesterone acetate and megestrol acetate; and (i) thyroid hormones such as le
  • Molecular targeted agents include (a) receptor tyrosine kinase ('RTK') inhibitors, such as inhibitors of EGFR, including erlotinib, gefitinib, and neratinib; inhibitors of VEGFR including vandetanib, semaxinib, and cediranib; and inhibitors of PDGFR; further included are RTK inhibitors that act at multiple receptor sites such as lapatinib, which inhibits both EGFR and HER2, as well as those inhibitors that act at of each of C-kit, PDGFR and VEGFR, including but not limited to axitinib, sunitinib, sorafenib and toceranib; also included are inhibitors of BCR-ABL, c-kit and PDGFR, such as imatinib; (b) FKBP binding agents, such as an immunosuppressive macrolide antibiotic, including bafilomycin, rapamycin (sirolimus) and everolimus; (
  • phenotype -directed therapy agents including: monoclonal antibodies such as alemtuzumab, bevacizumab, cetuximab, ibritumomab tiuxetan, rituximab, and trastuzumab; (e) immunotoxins such as gemtuzumab ozogamicin; (f) radioimmunoconjugates such as 1311-tositumomab; and (g) cancer vaccines.
  • PI3K/mTOR inhibitors such as, for example, BEZ-235, PX-866, D 106669, CAL 101, GDC0941, SF1126, SF2523 are also identified in the art as PI3K/mTOR inhibitors; additional examples, such as PI-103 [3-[4-(4- mo holinylpyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride] are well-known to those of skill in the art. Additional well-known PI3K inhibitors include LY294002 [2-(4- morpholinyl)-8-phenyl-4H-l-benzopyran-4-one] and wortmannin.
  • mTOR inhibitors known to those of skill in the art include temsirolimus, deforolimus, sirolimus, everolimus, zotarolimus, and biolimus A9.
  • a representative subset of such inhibitors includes temsirolimus, deforolimus, zotarolimus, and biolimus A9.
  • HDAC inhibitors include, but are not limited to, (i) hydroxamic acids such as Trichostatin A, vorinostat (suberoylanilide hydroxamic acid (SAHA)), panobinostat (LBH589) and belinostat (PXD101) (ii) cyclic peptides, such as trapoxin B, and depsipeptides, such as romidepsin (NSC 630176), (iii) benzamides, such as MS-275 (3-pyridylmethyl-N- ⁇ 4-[(2- aminophenyl)-carbamoyl] -benzyl ⁇ -carbamate), CI994 (4-acetylamino-N-(2aminophenyl)- benzamide) and MGCD0103 (N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2- ylamino)methyl)benzamide), (i) hydrox
  • Hsp90 inhibitors include, but are not limited to, benzoquinone ansamycins such as geldanamycin, 17 DMAG (17-Dimethylamino-ethylamino-17-demethoxygeldanamycin), tanespimycin (17 AAG, 17-allylamino-17 demethoxygeldanamycin), EC5, retaspimycin (IPI- 504, 18,21 didehydro-17-demethoxy-18,21-dideoxo-18,21-dihydroxy-17-(2 propenylamino)- geldanamycin), and herbimycin; pyrazoles such as CCT 018159 (4-[4-(2,3-dihydro-l,4- benzodioxin-6-yl)-5-methyl-lH-pyrazol-3-yl]-6-ethyl-l,3-benzenediol); macrolides, such as radicocol; as well as BIIB021 (CNF2024),
  • PARP inhibitors include, but are not limited to, 4-(3-(l- (cyclopropanecarbonyl)piperazine-4-carbonyl)-4-fluorobenzyl)phthalazin-l(2H)-one (olaparib, AZD2281, Ku-0059436), 2-[(2R)-2-methylpyrrolidin-2-yl]-lH-benzimidazole-4- carboxamide (Veliparib, ABT-888), (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH- l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (talazoparib, BMN 673), 4-iodo-3-nitrobenzamide (iniparib, BSI-201), 8-fluoro-5-(4-
  • Miscellaneous agents include altretamine, arsenic trioxide, gallium nitrate, hydroxyurea, levamisole, mitotane, octreotide, procarbazine, suramin, thalidomide, photodynamic compounds such as methoxsalen and sodium porfimer, and proteasome inhibitors such as bortezomib.
  • combination therapies including the use of protective or adjunctive agents, including: cytoprotective agents such as armifostine, dexrazonxane, and mesna, phosphonates such as peridronate and zoledronic acid, and stimulating factors such as epoetin, darbeopetin, filgrastim, PEG- filgrastim, and sargramostim, are also envisioned.
  • protective or adjunctive agents including: cytoprotective agents such as armifostine, dexrazonxane, and mesna, phosphonates such as peridronate and zoledronic acid, and stimulating factors such as epoetin, darbeopetin, filgrastim, PEG- filgrastim, and sargramostim.
  • one or more additional therapeutically active agents can include immunotherapy, anti-angiogenics, and radiotherapy.
  • a pharmaceutical composition comprising one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, and a pharmaceutically acceptable excipient or adjuvant.
  • the pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes.
  • a pharmaceutical composition comprising one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, further comprises a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
  • excipients can be used to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient.
  • An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach.
  • the formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
  • the pharmaceutical compositions of the present disclosure may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels.
  • the pharmaceutical compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • additional materials useful in physically formulating various dosage forms of the compositions of the present invention such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • such materials when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention.
  • the formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.
  • the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques.
  • Intraarterial and intravenous injection as used herein includes administration through catheters.
  • the compounds disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the compounds disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • a suitable vehicle e.g., sterile pyrogen- free water
  • suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA, the entire disclosure of which is incorporated by reference herein for all purposes.
  • a pharmaceutical composition of the present disclosure is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, as disclosed herein, combined with a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05M phosphate buffer or 0.8% saline.
  • Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
  • non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.
  • Oral carriers can be elixirs, syrups, capsules, tablets and the like.
  • Liquid carriers suitable for use in the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration.
  • the liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
  • the powders and tablets preferably contain up to 99% of the active compound.
  • suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • Parenteral carriers suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like.
  • Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • Carriers suitable for use in the present application can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
  • the carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.
  • Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition and/or combination, and may make a pharmaceutical dosage form containing the composition and/or combination easier for the patient and care giver to handle.
  • Diluents for solid compositions and/or combinations include, for example, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • microcrystalline cellulose e.g., AVICEL
  • microfine cellulose e.g., lactose, starch, pregelatinized starch
  • calcium carbonate calcium sulfate
  • sugar dextrates
  • dextrin dextrin
  • dextrose dibasic calcium phosphate dihydrate
  • a pharmaceutical composition of the present invention is a solid (e.g., a powder, tablet, a capsule, granulates, and/or aggregates).
  • a solid pharmaceutical composition comprising one or more ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions and/or combinations include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.
  • carbomer e.g., carbopol
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition and/or combination.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB), potato starch, and starch.
  • a disintegrant include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.
  • Glidants can be added to improve the flowability of a non-compacted solid composition and/or combination and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet is made by the compaction of a powdered composition
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition and/or combination to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • a pharmaceutical composition of the present invention is a liquid (e.g., a suspension, elixir and/or solution).
  • a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • Liquid pharmaceutical compositions can be prepared using compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene- polyoxypropylene copolymers can be useful excipients to control the release of active compounds.
  • Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
  • Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition and/or combination an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions and/or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
  • Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition can also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
  • compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer.
  • the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent.
  • the compound can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water.
  • an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
  • a pharmaceutical composition of the present invention is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example an emulsion in an acceptable oil
  • ion exchange resins for example an emulsion in an acceptable oil
  • sparingly soluble derivatives for example, as a sparingly soluble salt.
  • a pharmaceutical composition of the present invention comprises a delivery system.
  • delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.
  • a pharmaceutical composition of the present invention comprises a co-solvent system.
  • co-solvent systems comprise, for example, benzyl alcohol, anonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • co-solvent systems are used for hydrophobic compounds.
  • VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80 and 65% w/v polyethylene glycol 300.
  • co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
  • identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • a pharmaceutical composition of the present invention comprises a sustained-release system.
  • a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers.
  • sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks or months.
  • compositions of the present disclosure can be determined according to any clinically-acceptable route of administration of the composition to the subject.
  • the manner in which the composition is administered is dependent, in part, upon the cause and/or location.
  • One skilled in the art will recognize the advantages of certain routes of administration.
  • the method includes administering an effective amount of the agent or compound (or composition comprising the agent or compound) to achieve a desired biological response, e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, a symptom of a condition to be treated, e.g., oncology and neurology disorders.
  • the route of administration is systemic, e.g., oral or by injection.
  • a pharmaceutical composition of the present disclosure is prepared for oral administration.
  • a pharmaceutical composition is formulated by combining one or more agents and pharmaceutically acceptable carriers. Certain of such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject.
  • Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • such a mixture is optionally ground and auxiliaries are optionally added.
  • pharmaceutical compositions are formed to obtain tablets or dragee cores.
  • disintegrating agents e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate are added.
  • compositions for oral administration are push- fit capsules made of gelatin.
  • Certain of such push-fit capsules comprise one or more pharmaceutical agents of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • one or more pharmaceutical agents of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • compositions are prepared for buccal administration. Certain of such pharmaceutical compositions are tablets or lozenges formulated in conventional manner.
  • a pharmaceutical composition is prepared for transmucosal administration.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • a pharmaceutical composition is prepared for administration by inhalation.
  • Certain of such pharmaceutical compositions for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer.
  • Certain of such pharmaceutical compositions comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined with a valve that delivers a metered amount.
  • capsules and cartridges for use in an inhaler or insufflator may be formulated.
  • Certain of such formulations comprise a powder mixture of a pharmaceutical agent of the invention and a suitable powder base such as lactose or starch.
  • the compound of the present disclosure are administered by the intravenous route.
  • the parenteral administration may be provided in a bolus or by infusion.
  • a pharmaceutical composition is prepared for rectal administration, such as a suppository or retention enema.
  • Certain of such pharmaceutical compositions comprise known ingredients, such as cocoa butter and/or other glycerides.
  • a pharmaceutical composition is prepared for topical administration.
  • Certain of such pharmaceutical compositions comprise bland moisturizing bases, such as ointments or creams.
  • ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, and lanolin and water in oil emulsions.
  • suitable cream bases include, but are not limited to, cold cream and hydrophilic ointment.
  • the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
  • one or more compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof are formulated as a prodrug.
  • a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically more active form.
  • prodrugs are useful because they are easier to administer than the corresponding active form.
  • a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form.
  • a prodrug may have improved solubility compared to the corresponding active form.
  • prodrugs are less water soluble than the corresponding active form. In certain instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility.
  • a prodrug is an ester. In certain such embodiments, the ester is metabolically hydrolyzed to carboxylic acid upon administration. In certain instances the carboxylic acid containing compound is the corresponding active form.
  • a prodrug comprises a short peptide (polyaminoacid) bound to an acid group. In certain of such embodiments, the peptide is cleaved upon administration to form the corresponding active form.
  • a prodrug is produced by modifying a pharmaceutically active compound such that the active compound will be regenerated upon in vivo administration.
  • the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • the amount of the compounds of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof can be administered at about 0.001 mg/kg to about 100 mg/kg body weight (e.g., about 0.01 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 5 mg/kg).
  • the concentration of a disclosed compound in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration.
  • the agent may be administered in a single dose or in repeat doses.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. Treatments may be administered daily or more frequently depending upon a number of factors, including the overall health of a patient, and the formulation and route of administration of the selected compound(s). An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form, such unit dosage form can contain from about 1 mg/kg of compound to about 500 mg/kg of compound, and can be given in a single dose or in two or more doses.
  • Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, trans- dermally, or any other methods as disclosed herein.
  • the compounds or pharmaceutical compositions of the present disclosure may be coadministered with one or more therapeutically active agent, such as chemotherapeutic agents and immunotherapeutic agents.
  • therapeutically active agent such as chemotherapeutic agents and immunotherapeutic agents.
  • co-administration refers to administration of (a) compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, and (b) at least one additional therapeutically active agent, together in a coordinated fashion.
  • the coadministration can be simultaneous administration, sequential administration, overlapping administration, interval administration, continuous administration, or a combination thereof.
  • the compound of the present disclosure and at least one additional therapeutically active agent are formulated into a single dosage form.
  • the compound of the present disclosure and at least one additional therapeutically active agent are provided in a separate dosage forms.
  • the co-administration is carried out for one or more treatment cycles.
  • treatment cycle it is meant a pre-determined period of time for co-administering the compound of the present disclosure (e.g., a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof) and at least one therapeutically active agent.
  • the patient is examined at the end of each treatment cycle to evaluate the effect of the present combination therapy.
  • the co-administration is carried out for 1 to 48 treatment cycles.
  • the co-administration is carried out for 1 to 36 treatment cycles.
  • the co-administration is carried out for 1 to 24 treatment cycles.
  • each of the treatment cycle has about 3 or more days. In another embodiment, each of the treatment cycle has from about 3 days to about 60 days. In another embodiment, each of the treatment cycle has from about 5 days to about 50 days. In another embodiment, each of the treatment cycle has from about 7 days to about 28 days. In another embodiment, each of the treatment cycle has 28 days. In one embodiment, the treatment cycle has about 29 days. In another embodiment, the treatment cycle has about 30 days. In another embodiment, the treatment cycle has about a month-long treatment cycle. In another embodiment, the treatment cycle has from about 4 to about 6 weeks.
  • the dosing frequency for each of the compound of the present disclosure may vary from once per day to six times per day. That is, the dosing frequency may be once per day, twice per day, three times per day, four times per day, five times per day, or six times per day. In some embodiments, dosing frequency may be one to six times per week or one to four times per month. In one embodiment, dosing frequency may be once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.
  • void day there may be one or more void days in a treatment cycle.
  • void day it is meant a day when neither the compound of the present disclosure (e.g., a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof) or at least one therapeutically active agent is administered.
  • any treatment cycle must have at least one non-void day.
  • non- void day it is meant a day when at least one of the compound of the present disclosure and at least one therapeutically active agent is administered.
  • the compound of the present disclosure e.g., a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof) and at least one therapeutically active agent are administered on the same day.
  • the compound of the present disclosure and at least one therapeutically active agent can be administered at the same time or one at a time.
  • the administration of the compound of the present disclosure and at least one therapeutically active agent occurs within 24 hours or less.
  • the compound of the present disclosure e.g., a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof
  • the at least one additional therapeutically active agent is administered 1 to 4 times per day, 1 to 4 times per week, once every two weeks, once every three weeks, once every four weeks or 1 to 4 times per month.
  • the compound of the present disclosure is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once a month; and the at least one additional therapeutically active agent is administered 1 to 4 times per day, 1 to 4 times per week, once every two weeks, once every three weeks, once every four weeks or 1 to 4 times per month.
  • sequential administration it is meant that during a period of two or more days of continuous co-administration without any void day, only one of the compound of the present disclosure (e.g., a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof) and at least one therapeutically active agent is administered on any given day.
  • a compound of formula (A), (B), (I), or (II) and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof
  • the compound of the present disclosure e.g., a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof
  • at least one additional therapeutically active agent is administered 1 to 4 times per day, 1 to 4 times per week, once every two weeks, once every three weeks, once every four weeks or 1 to 4 times per month.
  • the compound of the present disclosure is administered from once a week, once every two weeks, once every three weeks, once every four weeks, or once a month; and at least one additional therapeutically active agent is administered 1 to 4 times per day, 1 to 4 times per week, once every two weeks, once every three weeks, once every four weeks or 1 to 4 times per month.
  • overlapping administration it is meant that during a period of two or more days of continuous co-administration without any void day, there is at least one day of simultaneous administration and at least one day when only one of the compound of the present disclosure (e.g., a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof) and at least one therapeutically active agent is administered.
  • the compound of the present disclosure e.g., a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof
  • interval administration it is meant a period of co-administration with at least one void day.
  • continuous administration it is meant a period of co-administration without any void day.
  • the continuous administration may be simultaneous, sequential, or overlapping, as described above.
  • the co-administration comprises oral administration, parenteral administration, or a combination thereof.
  • parenteral administration include, but are not limited to intravenous (IV) administration, intraarterial administration, intramuscular administration, subcutaneous administration, intraosseous administration, intrathecal administration, or a combination thereof.
  • IV intravenous
  • the compound of the present disclosure e.g., a compound of formula (A), (B), (I), or (II), and any subgenera thereof, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof
  • at least one therapeutically active agent can be independently administered orally or parenterally.
  • the compound of the present disclosure and at least one therapeutically active agent is administered parenterally.
  • the parenteral administration may be conducted via injection or infusion.
  • an effective dosage can a ' depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated.
  • a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.
  • the dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.
  • Step 2 Synthesis of 5,5-dimethylpyrrolidin-2-one (Compound 4)
  • Step 4 Synthesis of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine (Compound 8)
  • Step 5 Synthesis of (£)-4-bromo-N-(5,5-dimethylpyrrolidin-2-ylidene)-2,6- difluoro
  • Step 6 Synthesis of 7-bromo-5-fluoro-l,l-dimethyl-2,3-dihydro-lH- benzo[t/]pyrrolo[l,2- ]imidazole (Compound 11)

Abstract

La présente invention concerne un composé de formule (I), ou un sel, un solvate, un stéréoisomère ou un tautomère pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique comprenant un composé de formule (A) ou de formule (B), et tous les sous-genres de ceux-ci, et l'utilisation desdits composés associés et desdites compositions associées, où R1, R2, R3a, R3b, R5, R6, X1, X2, Y et n sont décrits dans la description.
PCT/IB2018/056140 2017-08-15 2018-08-15 Inhibiteurs de cdk4/6 et leur utilisation WO2019035008A1 (fr)

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WO2022113003A1 (fr) 2020-11-27 2022-06-02 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk
WO2022149057A1 (fr) 2021-01-05 2022-07-14 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk

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WO2022113003A1 (fr) 2020-11-27 2022-06-02 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk
WO2022149057A1 (fr) 2021-01-05 2022-07-14 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk

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